20-3694851-T-G

Variant names:

• chr20-3694851-T-G
• rs709012
• NM_023068.4:c.2756A>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_023068.4(SIGLEC1):​c.2756A>C​(p.His919Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.64 in 1,613,124 control chromosomes in the GnomAD database, including 334,095 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.69 (36578 hom., cov: 33)
  • Exomes 𝑓: 0.63 (297517 hom.)
• Consequence: SIGLEC1 NM_023068.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.92
• Publications: 40 publications found

Genes affected

SIGLEC1 (HGNC:11127): (sialic acid binding Ig like lectin 1) This gene encodes a member of the immunoglobulin superfamily. The encoded protein is a lectin-like adhesion molecule that binds glycoconjugate ligands on cell surfaces in a sialic acid-dependent manner. It is a type I transmembrane protein expressed only by a subpopulation of macrophages and is involved in mediating cell-cell interactions. The protein plays an important role in multiple human diseases and bacterial and viral infections has been shown to enhance SARS-CoV-2 infection. [provided by RefSeq, Dec 2021]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=8.4370726E-7).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.841 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SIGLEC1	NM_023068.4	c.2756A>C	p.His919Pro	missense_variant	Exon 12 of 22	ENST00000344754.6	NP_075556.1
SIGLEC1	NM_001367089.1	c.2756A>C	p.His919Pro	missense_variant	Exon 11 of 20		NP_001354018.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SIGLEC1	ENST00000344754.6	c.2756A>C	p.His919Pro	missense_variant	Exon 12 of 22	1	NM_023068.4	ENSP00000341141.4
SIGLEC1	ENST00000707083.1	c.2756A>C	p.His919Pro	missense_variant	Exon 11 of 20			ENSP00000516734.1

Frequencies

GnomAD3 genomes AF: 0.688 AC: 104664 AN: 152046 Hom.: 36535 Cov.: 33

Gnomad AFR AF: 0.777

Gnomad AMI AF: 0.386

Gnomad AMR AF: 0.694

Gnomad ASJ AF: 0.575

Gnomad EAS AF: 0.863

Gnomad SAS AF: 0.698

Gnomad FIN AF: 0.760

Gnomad MID AF: 0.567

Gnomad NFE AF: 0.619

Gnomad OTH AF: 0.661

GnomAD2 exomes AF: 0.686 AC: 171833 AN: 250518 AF XY: 0.679

Gnomad AFR exome AF: 0.782

Gnomad AMR exome AF: 0.746

Gnomad ASJ exome AF: 0.583

Gnomad EAS exome AF: 0.875

Gnomad FIN exome AF: 0.760

Gnomad NFE exome AF: 0.621

Gnomad OTH exome AF: 0.654

GnomAD4 exome AF: 0.635 AC: 927687 AN: 1460960 Hom.: 297517 Cov.: 52 AF XY: 0.636 AC XY: 462328 AN XY: 726798

African (AFR) AF: 0.780 AC: 26115 AN: 33474

American (AMR) AF: 0.740 AC: 33087 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.587 AC: 15333 AN: 26136

East Asian (EAS) AF: 0.826 AC: 32801 AN: 39698

South Asian (SAS) AF: 0.681 AC: 58766 AN: 86252

European-Finnish (FIN) AF: 0.751 AC: 39585 AN: 52700

Middle Eastern (MID) AF: 0.583 AC: 3362 AN: 5768

European-Non Finnish (NFE) AF: 0.611 AC: 679509 AN: 1111848

Other (OTH) AF: 0.648 AC: 39129 AN: 60386

GnomAD4 genome AF: 0.688 AC: 104756 AN: 152164 Hom.: 36578 Cov.: 33 AF XY: 0.697 AC XY: 51854 AN XY: 74386

African (AFR) AF: 0.777 AC: 32259 AN: 41514

American (AMR) AF: 0.695 AC: 10624 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.575 AC: 1995 AN: 3470

East Asian (EAS) AF: 0.863 AC: 4463 AN: 5174

South Asian (SAS) AF: 0.698 AC: 3365 AN: 4820

European-Finnish (FIN) AF: 0.760 AC: 8048 AN: 10594

Middle Eastern (MID) AF: 0.555 AC: 162 AN: 292

European-Non Finnish (NFE) AF: 0.619 AC: 42102 AN: 67980

Other (OTH) AF: 0.656 AC: 1386 AN: 2112

Alfa AF: 0.637 Hom.: 145947

Bravo AF: 0.685

TwinsUK AF: 0.605 AC: 2243

ALSPAC AF: 0.610 AC: 2352

ESP6500AA AF: 0.766 AC: 3376

ESP6500EA AF: 0.615 AC: 5293

ExAC AF: 0.682 AC: 82829

Asia WGS AF: 0.755 AC: 2626 AN: 3478

EpiCase AF: 0.610

EpiControl AF: 0.609

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.031
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	17
DANN	Benign	0.22
DEOGEN2	Benign	0.044	T
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.0082	N
LIST_S2	Benign	0.10	T
MetaRNN	Benign	8.4e-7	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-1.4	N
PhyloP100		2.9
PrimateAI	Benign	0.41	T
PROVEAN	Benign	0.92	N
REVEL	Benign	0.073
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.11
MPC		0.17
ClinPred		0.011	T
GERP RS		4.8
Varity_R		0.14
gMVP		0.46
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs709012; hg19: chr20-3675498; COSMIC: COSV52468518; COSMIC: COSV52468518;